Discovery DMPK Quick Guide: Guide to Data Interpretation and integration

Foreword
Contents
About the Authors
Other Contributors
List of Figures
List of Tables
Chapter 1: Goals for DMPK During Drug Optimizations
1.1 ADME Objectives
1.2 Expertise Needed During Drug Discovery
1.3 Optimization of ADME Properties
1.4 Modern ADME Optimization
References
Chapter 2: Drug Properties
2.1 Impact of Physicochemical Properties on ADME Parameters
2.1.1 Structure-Based Design
2.1.2 Property-Based Design
2.2 Solubility
2.3 Multi-Parameter Optimization (MPO)
2.4 Drug Properties and Therapeutic Targets
2.4.1 G Protein-Coupled Receptor (GPCR)-Targeted Drugs
2.4.2 Kinase Inhibitors
2.4.3 Covalent Inhibitors
2.4.4 Deuterated Drugs
2.4.5 Peptides and Macrocyclic Peptides
2.4.6 Chimeric Degraders
2.4.7 Prodrugs
2.5 Metabolites as a Source of New Drugs
2.5.1 Secondary Metabolites from Natural Products
2.5.2 Active Metabolites
2.5.3 Targeted Approach for Active Metabolite Screening and Generation
References
Chapter 3: DMPK Lead Optimization
3.1 Pharmacokinetics
3.1.1 Basic PK Terminology
3.1.1.1 Basic PK Terminologies Are Described Below
3.1.2 PK Parameters and Drug Selection
3.1.2.1 Half-Life and Accumulation
3.1.2.2 Oral Bioavailability
3.1.2.3 Animal Selection for Preclinical Studies
3.1.2.4 Higher Throughput PK Studies for Drug Selection
3.1.2.5 Cassette (or N-in-1) Dosing Studies
3.1.2.6 Cassette Accelerated Rapid Rat Studies (Carrs) or Snapshot PK
3.2 Use of In Silico ADME Models in Drug Discovery
3.3 Isosteres
3.4 Metabolic Clearance Optimization
3.4.1 Optimization Based on Drug Metabolism Enzymes
3.4.1.1 Cytochrome P450 Enzymes (CYP or P450)
3.4.1.2 Aldehyde Oxidase (AO)
3.4.1.3 Flavin Containing Monooxygenase (FMO)
3.4.1.4 Epoxide Hydrolase (EH)
3.4.1.5 Uridine Diphosphate Glucuronosyltransferases (UGT)
3.4.2 Optimization Based on Metabolism of Isosteres
3.5 Permeability and Drug Transporters
3.5.1 Basic Concepts and Definitions
3.5.2 Localization of Select Transporters
3.5.3 Transporters of Interest for Evaluation
3.6 What Role Does Plasma Protein Binding Play in Drug Discovery?
3.7 Reactive Metabolites: Bioactivation
3.8 Supplemental Materials
References
Chapter 4: Candidate Translational Characterization
4.1 Basic Concepts
4.2 Prediction of Human Pharmacokinetics
4.2.1 Human PK Prediction Based on In Vivo Preclinical PK Studies
4.2.2 Simple Allometry for Prediction of Human CL
4.2.3 The Rule of Exponents
4.2.4 Other Human CL Prediction Methods Based on Allometric Principles
4.2.5 Two Species Allometry
4.2.5.1 Allometry with Unbound Clearance (CLu)
4.2.5.2 Tang and Mayersohn (2005)
4.2.6 Single Species Scaling
4.2.7 Single Species Liver Blood Flow Method
4.2.8 Simple Allometry for Prediction of Human Vd
4.2.9 Other Human Vd Prediction Methods Based on Allometric Principles
4.2.9.1 Allometry with Unbound Clearance (Vd u)
4.2.10 Single Species Scaling
4.2.11 Human PK Prediction Based on In Vitro Studies
4.2.12 In Vitro Methods of Determining Intrinsic Clearance
4.2.13 Determination of Intrinsic Clearance Using Michaelis-Menten Kinetic Parameters
4.2.14 Determination of Intrinsic Clearance Using Substrate Depletion Method at a Single Substrate Concentration (In Vitro t1/2 Method)
4.2.15 Scaling Factors for In Vitro-In Vivo Extrapolation
4.2.16 Liver Models for Estimation of Hepatic Clearance
4.2.17 Oie-Tozer Method for Prediction of Volume of Distribution
4.2.18 Prediction of Human Fraction Absorbed
4.2.19 Context of Confidence in Human PK Predictions
4.3 Pharmacokinetic/ Modeling and Human Dose Prediction
4.3.1 Pharmacodynamic Endpoint
4.3.2 Delayed Onset of Pharmacodynamic Effect and the Counter-Clockwise Hysteresis
4.4 Physiologically-Based Pharmacokinetic Models
4.5 Toxicokinetics and Safety Margins
4.5.1 Toxicokinetics
4.5.2 Safety Margins
References
Chapter 5: Q&A of DMPK Issues and Tools for Drug Discovery
5.1 ADME Discovery Strategy
5.1.1 What Is the Minimum Set of In Vitro Assays Needed During the Drug Discovery Process?
5.1.2 Should Plasma Protein Binding (PPB) Be Optimized to Improve PK?
5.1.3 Can Drug Delivery Systems Save a Challenging ADME Drug?
5.1.4 How to Select Toxicity Species at the Drug Discovery Stage?
5.1.5 What Are the ADME Challenges to Be Considered with New Modalities?
5.2 Metabolism-Related Concerns
5.2.1 How to Determine the Safety Contribution of Metabolites?
5.2.2 Is the Presence of Circulating Metabolites a Concern in Preclinical Species?
5.2.3 When to Perform Reaction Phenotyping?
5.2.4 What Are the Challenges for Drugs for Which Glucuronidation or Aldehyde Oxidase Oxidation is the Major Route of Clearance?
5.2.5 What to Do When a Compound Is Stable in In Vitro Metabolic Systems, but Has High Clearance In Vivo?
5.2.6 How to Determine the Contribution of Metabolism (CLm) to the Total In Vivo Clearance Pathways?
5.3 Drug Transporter-Related Concerns
5.3.1 What Drug Transporters Could Be Subject to Drug-Drug Interaction?
5.3.2 Do Transporters Affect Drug Absorption and Tissue Distribution?
5.3.3 Can Drug Transporters Play an Important Role in Drug Clearance?
References
Chapter 6: ADME Assays
6.1 Overview of ADME Assays and Their Placement in the Discovery Cascade
6.2 In Vitro Assays
6.2.1 Metabolic Stability
6.2.2 The Metabolic Stability Assay
6.2.3 Reaction Phenotyping
6.2.4 Reactive Metabolite Trapping Studies
6.2.4.1 Chemical Trapping Agents
6.2.5 Metabolite Identification
6.2.6 Permeability and Transport
6.2.7 Plasma Protein Binding
6.2.8 Drug Metabolizing Enzyme Inhibition
6.2.9 Drug Metabolizing Enzyme Induction
6.2.10 Blood to Plasma Partitioning
6.3 In Vivo Pharmacokinetics
6.4 Bioanalysis
6.5 Supplemental Tables
References
Chapter 7: Regulatory Documents for IND to Support FIH
7.1 Regulatory Authorities in Different Countries
7.2 Code of Federal Regulations (US)
7.3 IND Sections
7.4 Notable FDA Guidance for Industry
7.5 Regulatory Pathways: 505(b)(1) and 505(b)(2)
Appendix
Chemical Nomenclature
General Nomenclature for Organic Compounds
Five-Membered Heterocyclic Rings
Six-Membered Heterocyclic Rings
Bicyclic Heterocycles
Index